Thienopyranecarboxamide derivatives

ABSTRACT

The invention relates to novel N-(substituted phenyl)-N′-[ω-(5-substituted-7-oxo-7H-thieno[3,2-b]pyran-3-carbonylamino)alkyl]piperazines their N-oxides and pharmaceutically acceptable salts thereof. The compounds are endowed with enhanced selectivity for alpha 1 -adrenergic receptors and a low activity in lowering blood pressure. The compounds are useful in the treatment of obstructive syndromes of the lower urinary tract, including benign prostatic hyperplasia (BPH), and in the treatment of lower urinary tract symptoms (LUTS) and neurogenic lower urinary tract dysfunction (NLUTD). The compounds are also useful in the treatment of excessive intraocular pressure, cardiac arrhythmia, erectile dysfunction, sexual dysfunction, and for inhibiting cholesterol synthesis or reducing sympathetically mediated pain.

The enclosed application is based on Provisional Patent ApplicationSerial No. 60/179,423. Applicants claim the benefit of the filing dateof the aforesaid Provisional Application under 35 U.S.C. §119(e)(1).

SCOPE OF THE INVENTION

The present invention relates to thienopyranecarboxamide derivatives, topharmaceutical compositions containing them and to uses for suchderivatives and compositions.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,403,842, Leonardi et al., and its continuations in part(U.S. Pat. Nos. 5,474,994 and 5,605,896) claim heterobicyclicderivatives bearing substituted phenylpiperazines as basic moietieslinked to the heterocyclic ring by a variety of spacer groups. Amongsaid derivatives, compound A (Ex. 11) is of relevant interest due itsvery high uroselective activity.

Compound A is endowed with good affinity for the α_(1A) adrenoceptor andis able to selectively inhibit contractility of the prostatic urethra ina dog model without substantial effects on blood pressure (Leonardi etal., J. Pharmacol. Exp. Therap., 281:1272-1283, 1997.)

7-Oxo-7H-thieno[3,2-b]pyran-3-carboxylic acid and itsN,ω-aminoalkylamides are compounds not yet reported in the literature.The present invention is directed to the new structural class of theN-(substitutedphenyl)-N′-[ω-(5-substituted-7-oxo-7H-thieno[3,2-b]pyran-3-carbonylamino)alkyl]piperazines.

Compounds of this class are endowed with enhanced selectivity toward theα₁ adrenergic receptor, in particular with respect to the 5-HT_(1A)receptor, and improved in vivo uroselectivity even compared to compoundA, with remarkable effects on relaxation of prostatic urethra and verylow activity in lowering blood pressure. This activity profile suggeststhe safer use of the compounds of the invention in the therapy ofobstructive syndromes of the lower urinary tract, including benignprostatic hyperplasia (BPH), without side-effects associated withhypotensive activity.

SUMMARY OF THE INVENTION

In one aspect, the invention is directed to compounds of Formula I:

wherein

R is an aryl, cycloalkyl or polyhaloalkyl group,

R₁ is chosen from the group consisting of alkyl, alkoxy,polyfluoroalkoxy, hydroxy and trifluoromethanesulfonyloxy; each of R₂and R₃ independently is chosen from the group consisting of a hydrogen,halogen, alkoxy and polyfluoroalkoxy group, and n is 0, 1 or 2.

The preferred aryl group which R may represent without limitation isphenyl. The preferred cycloalkyl group that R may represent withoutlimitation is cyclohexyl. The preferred polyhaloalkyl group that R mayrepresent without limitation is trifluoromethyl. The preferred alkylgroup which R₁ may represent without limitation is C₁₋₄ lower alkyl.Preferred alkoxy groups (C₁₋₄) which R₁, R₂, and R₃ may representwithout limitation are lower alkoxy groups, most preferably methoxy.Preferred polyfluoroalkoxy which R₁, R₂, and R₃ may represent withoutlimitation are trifluoromethoxy or 2,2,2-trifluoroethoxy.

The preferred value for n is 1.

The invention further provides pharmaceutical compositions comprising acompound of Formula I or a N-oxide or pharmaceutically acceptable saltof such a compound in admixture with a pharmaceutically acceptablediluent or carrier.

In another aspect, the present invention is directed to methods forselectively preventing contractions (including noradrenaline-mediatedcontractions) of the urethra and lower urinary tract, withoutsubstantially affecting blood pressure, by administering one or moreselected compounds of Formula I to a mammal (including a human) in needof such treatment in an amount or amounts effective for the particularuse.

In yet another aspect, the invention is directed to methods for blockingα₁ receptors, by delivering to the environment of said receptors, e.g.,to the extracellular medium, (or by administering to a mammal possessingsaid receptors) an effective amount of a compound of the invention, inthis way relieving diseases associated to overactivity of saidreceptors.

The very high uroselectivity of the compounds of this invention has beentested in the dog model described in Example 10, where their efficacy inantagonizing the contractions of prostatic urethra in the presence ofvery limited effects on blood pressure has been shown, in comparison tocompound A and to another well-known α₁-antagonist, prazosin.

Accordingly, it is a primary object of the present invention to providea method of treating BPH which avoids any undue side effects due toacute hypotension (i.e., limited effects on blood pressure).

It is another object of the present invention to provide pharmaceuticalcompositions comprising 7-oxo-7H-thieno[3,2-b] pyran compounds which areselective α₁ adrenoceptor antagonists, which compositions are effectivefor the treatment of BPH optionally including a carrier or diluent.

It is another object of the present invention to provide a method oftreating BPH using 7-oxo-7H-thieno[3,2-b] pyran compounds which areselective α₁ adrenoceptor antagonists.

Another aspect of the invention is the use of new compounds for loweringintraocular pressure, and the treatment of cardiac arrhythmia anderectile dysfunction.

Other features and advantages of the present invention will be apparentto those skilled in the art from the following detailed description andclaims.

DETAILED DESCRIPTION OF THE INVENTION

All patents, patent applications and literature references cited in thisapplication are incorporated by reference in their entirety.

The adrenergic antagonistic activity of the compounds of the inventionrenders them useful as agents acting on body tissues particularly richin α₁-adrenergic receptors (such as prostate and urethra). Accordingly,the anti-adrenergic compounds within the invention, established as suchon the basis of their receptor binding profile, can be usefultherapeutic agents for the treatment, for example, of micturitionproblems associated with obstructive disorders of the lower urinarytract, including but not limited to benign prostatic hypertrophy (BPH).

BPH is a progressive condition, which is characterised by a nodularenlargement of prostatic tissue resulting in obstruction of the urethra.This results in increased frequency of urination, nocturia, a poorurinary stream and hesitancy or delay in starting urine flow. Chronicconsequences of BPH can include hypertrophy of bladder smooth muscle, adecompensated bladder and an increased incidence of urinary tractinfection. The specific biochemical, histological and pharmacologicalproperties of a prostate adenoma leading to the bladder outletobstruction are not yet known. However, the development of BPH isconsidered to be an inescapable phenomenon for the ageing malepopulation. BPH is observed in approximately 70% of males over the ageof 70. Currently, the worldwide stated method of choice for treating BPHis surgery. A medicinal alternative to surgery is clearly verydesirable. The limitations of surgery for treating BPH include themorbidity rate of an operative procedure in elderly men, persistence orrecurrence of obstructive and irritative symptoms, as well as thesignificant cost of surgery.

α-Adrenergic receptors (McGrath et al., Med. Res. Rev., 9:407-533, 1989)are specific neuroreceptor proteins located in the peripheral andcentral nervous systems on tissues and organs throughout the body. Thesereceptors are important switches for controlling many physiologicalfunctions and, thus, represent important targets for drug development.In fact, many α-adrenergic drugs have been developed over the past 40years. Examples include clonidine, phenoxybenzamine and prazosin,terazosin, alfuzosin, doxazosin, tamsulosin (treatment of hypertension),naphazoline (nasal decongestant), and apraclonidine (treating glaucoma).α-Adrenergic drugs can be broken down into two distinct classes:agonists (clonidine and naphazoline are agonists), which mimic thereceptor activation properties of the endogenous neurotransmitternoradrenaline, and antagonists (phenoxybenzamine and prazosin,terazosin, alfuzosin, doxazosin, tamsulosin are antagonists), which actto block the effects of noradenaline. Many of these drugs are effective,but also produce unwanted side effects (for example, clonidine producesdry mouth and sedation in addition to its antihypertensive effects).

The above reported agonists are selective for the α₂ adrenergic receptorwhereas most antagonists are selective for the α₁ adrenoceptor, with theexception of tamsulosin which shows a relevant affinity also for the5-HT_(1A) receptor. Many of the cited α₁ antagonists are currently usedfor the therapy of BPH but, due to their poor uroselectivity, they areliable to cause side effects of cardiovascular type.

Recent pharmacological, biochemical and radioligand-binding studiesevidenced three different α₁-receptor subtypes with a high affinity forprazosin, namely α_(1A-)(α_(1A-)), α_(1B-)(α_(1b-)) andα_(1D-)(α_(1d-)), with lower case subscripts being used for recombinantreceptors and upper case subscripts for receptors in native tissues(Hieble et al., Pharmacol. Rev., 47:267-270, 1995). In functionalstudies α₁-receptors with a low affinity for prazosin have also beenidentified and termed α_(1L)-receptors (Flavahan and Vanhoutte, TrendsPharmacol. Sci., 7:347-349, 1986; Muramatsu et al., Pharmacol. Comm.,6:23-28, 1995).

Several studies have demonstrated the presence of these α₁-adrenergicreceptor subtypes in the lower-urinary-tract tissues as reviewed by(Andersson, K. E., “4th International Consultation in Benign ProstaticHyperplasia (BPH)”, Paris, Jul. 2-5, 1997, pages 601-609).

Several studies have shown that the human prostate receives innervationfrom both the sympathetic and parasympathetic nervous systems.

The adrenergic nerves are considered responsible for prostaticsmooth-muscle tone by releasing noradrenaline, stimulatingcontraction-mediating α-adrenoceptors. Approximately 50% of the totalurethral pressure in BPH patients may be due to α-adrenoceptor-mediatedmuscle tone. Functional studies have indicated the occurrence ofimportant adrenoceptor functions in prostatic adenomatous and capsulartissue. Clinical studies with the prototypical adrenoceptor-selectiveantagonist, prazosin, reinforced the key role of α₁ adrenoceptors in thecontrol of prostatic smooth-muscle tone. This was also confirmed in thelaboratory by studies showing that, although both α₁₋ and α₂₋adrenoceptors can be identified within the human prostate, contractileproperties are mediated primarily by α₁ adrenoceptors. Many clinicalinvestigations have confirmed that α₁-adrenoceptor blockade relieveslower urinary tract symptoms (LUTS), both of irritative and obstructivetype, in patients with BPH.

Two distinct α₁₋ adrenoceptor subtypes have been suggested to be presentin the human prostate, one with high (α_(1H)) and one with low (α_(1L))affinity for prazosin. All three high-affinity α₁ adrenoceptor subtypesfound in molecular cloning studies have been identified in prostaticstromal tissue. The α_(1a) subtype was found to be the dominant,representing about 60-85% of the α₁₋adrenoceptor population. Recentfindings suggest that there may be differences in subtype populationsbetween normal and hyperplastic prostates, the ratios between thesubtypes α_(1a):α_(1b):α_(1d) being 85:1:14 in BPH and 63:6:31 innon-BPH tissue.

The α_(1A-)adrenoceptor was reported to mediate the contractile responseof the human prostate in vitro. Ford et al. found that the α_(1A)adrenoceptor may not mediate contractile responses to noradrenaline, andsuggested as a candidate the α_(1L) adrenoceptor. Findings by Kenny etal. (Br. J. Pharmacol., 118:871-878, 1996) support the view that theα_(1L) adrenoceptor, which appears to share many of the characteristicsof an α_(1A) adrenoceptor, mediates the contractile response of thehuman prostate.

On the other hand, it has also been suggested that the α_(1A) and α_(1L)adrenoceptors may represent distinct pharmacological forms of the samereceptor.

The affinity of the compounds of the invention for each receptor can beassessed by receptor binding assays, for example as follows:

(1) α₁-adrenergic-receptor subtypes: using the specific ligand³H-prazosin, according to Testa et al., Pharmacol. Comm. 6: 79-86, 1995;Cotecchia, S., Schwinn, D. A., Randall, R. R. and Lefkowitz, F. J.,Proc. Natl. Acad. Sci. USA, 85: 7159-7163 (1988); Furchgott. R.E.,Handbook of Experimental Pharmacology—New Series, 283-335 (1972);Michel, M. C., Hanft, G. and Gross, G., Brit. J. Pharmacol. 111: 533-538(1994); Schwinn, D. A., Lomasney, J. W., Lorenz, W., Szklut, P. J.,Fremcau, R. T., Yang-Feng, T. L., Caron, M. G., Lefkowitz, R. J. andCotecchia, S., J Biol. Chem. 265: 8183-8189 (1990); Testa, R., Guarneri,L., Ibba, M., Strada, G., Poggesi, E., Taddei, C., Simonazzi, I. andLeonardi, A. Europ. J. Pharmacol. 249: 307-315 (1993).

(2) 5HT_(1A)-serotonergic receptor: using the specific ligand³H-8-OH-DPAT according to Fargin et al., Nature 335: 358-360, (1988);Kobilka, B. K. et al., Nature 329: 75-79 (1987); Cullen, B. R., Meth.Enzym. 152: 684-704 (1987); Gozlan, H. et al., J. Receptor Res. 7:195-221 (1987).

The α_(1L)-adrenergic receptor is not yet cloned and, therefore, thefunctional affinity of the compounds of the invention for this subtypecan be assessed by using an isolated organ preparation as reported byTesta et al., J. Pharmacol. Exp. Ther. 281: 1284-1293, (1997); Oshita,M., Kigoshi, S. and Muramatsu, I., Br. J. Pharmacol. 108: 1071-1076(1993).

In vitro testing of the compounds of this invention on the abovereceptors is described in Examples 8 and 9 below.

The drugs having α₁-adrenergic antagonistic activity currently used forthe symptomatic therapy of BPH are poorly subtype selective and subjectto cause relevant side effects due to their hypotensive activity.

Thus there is a need for selective α₁-antagonists which do not subjectthe BPH patient to the side effects, especially the cardiovascular sideeffects of said treatment.

The high uroselectivity of the compounds of the invention has beendemonstrated by the dog model of the Example 10 below, where theirefficacy in counteracting the contractions of prostatic urethra at dosesthat do not influence blood pressure has been shown.

SYNTHESIS OF THE COMPOUNDS OF THE INVENTION

The compounds according to the invention may be generally prepared asfollows:

Direct condensation of 7-oxo-7H-thieno[3,2-b]pyran-3-carboxylic acids ofthe formula I with the ω-aminoalkylamino derivatives 2 (SCHEME 1) leadsto the compounds of the invention. The condensation can be carried outin the presence of a condensing agent (e.g., dicyclohexylcarbodiimide ordiethyl cyanophosphonate) optionally in the presence of a promotingagent (e.g., N-hydroxysuccinimide, 4-dimethylaminopyridine orN,N′-carbonyldiimidazole) in an aprotic or chlorinated solvent (e.g.,N,N-dimethylformamide or chloroform) at −10/140° C. (Albertson, Org.React., 12:205-218, 1962; Doherty et al., J. Med. Chem., 35:2-14, 1992;Ishihara, Chem. Pharm. Bull., 39:3236-3243, 1991). In some cases theactivated ester or amide intermediates (such as O-(N-succinimidyl)esters or acyl imidazolides) can be isolated and further reacted with 2to be transformed into the corresponding amides (I) in an aprotic orchlorinated solvent at 10/100° C. This kind of condensation is wellillustrated in the Examples. Another activated intermediate which can beused is the mixed anhydride of 1, obtainable reacting 1 with an alkylchloroformate in the presence of a tertiary amine (e.g., triethylamineor N-methylmorpholine), which is reacted with 2 at 0-80° C.; optionallya promoting agent (e.g., 1-hydroxypiperidine) may be added before theamine addition (Albertson, Org. React., 12:157, 1962).

Alternatively the condensation can be carried out without a solvent at150-220° C. (Mitchell et al., J. Am. Chem. Soc., 53; 1879, 1931) or inhigh-boiling ethereal solvents (e.g., diglyme).

The condensation can also be performed through preparation and optionalisolation of reactive derivatives of 1 such as acyl halides. Formationof acyl halides of compounds of formula 1 and reactions with amines 2 toform amides is well documented in the literature and known to peopleskilled in the art.

Also less reactive derivatives of 1 can be used, such as alkyl esters,which in turn can be converted into I in the presence of a condensingagent (e.g., trimethylaluminum) in an aprotic and/or chlorinated solvent(e.g., hexane, dichloromethane) at −10/80° C., or without solvents at80-180° C., (Weinreb et al., Tetrahedron Lett., 4171, 1977; Lipton etal., Org. Synth., 59:49, 1979).

By the same methods of condensation reported above and usingH₂NCH₂(CH₂)_(n)CH₂X (with X=halogen or OH) as a reagent, 1 can betransformed into 3. In the case of X=OH, the alcoholic group is thenconverted into a suitable leaving group by methods well known to thoseskilled in the art. Compounds 3 (with X=leaving group such as halogen oralky/arylsulphonyloxy group) can be subsequently reacted with anappropriate phenylpiperazine 8 bearing the desired phenyl group. Thenucleophilic substitution is carried out preferably, but notnecessarily, at a temperature within the range of 20-200° C. in a polarsolvent such as dimethylformamide, acetonitrile, methanol, or withoutany solvent, usually in the presence of a base such as potassiumcarbonate. See also Gibson's chapter in Patai: “The Chemistry of theAmino Group”, p. 45 et seq., Wiley International Science, N.Y., 1968.

The preparation of compounds 2 which are not commercially available isdisclosed in the literature and is well known to those skilled in theart, and is usually carried out performing nucleophilic substitution ofa phenylpiperazine 8 on a N-(ω-haloalkyl)phthalimide or a properω-haloalkylnitrile or haloalkylamide by the method illustrated above forthe condensation of compounds 3 and 8, or by addition of an α,β-unsaturated alkylnitrile or alkylamide in a proper solvent (e.g.,acetonitrile, dimethylformamide, a chlorinated solvent or other aproticpolar solvent) at a temperature between 0° C. and the reflux temperatureof the solvent. Standard phthalimido-group deprotection or reduction ofthe amido or cyano group then provides compounds 2, and can be performedby methods well known to those skilled in the art.

The acids 1 of the invention in which R represents cycloalkyl or arylgroup can be synthesized (SCHEME 2) starting from methyl2-acetyl-3-hydroxythiophene-4-carboxylate (prepared as described in J.Chem. Soc. Perkin Trans I, 507, 1986), which can be esterified with theproper alkanoyl or aroyl chloride by using methods very well known tothose skilled in the art. Alternative procedures include the samemethods described above for the amidification of 1, which could beapplied as well in the esterification step to afford 4.

Monobromination of the methylketo group of 4 can afford 5, which canthen be reacted with triphenylphosphine (typically by reflux inacetonitrile, toluene, or other aprotic solvent), to give thephosphonium salt 6. A subsequent intramolecular ester-Wittig reactionapplied to this substrate yields the thieno[3,2-b]pyranes, 7.

Hydrolysis of the ester group of compounds 7 is accomplished by acid orbase catalysed procedures that are well known to those skilled in theart, yielding compounds 1.

Such hydrolysis procedures include the use of sodium hydroxide inaqueous ethanol at 40-75° C., or lithium hydroxide in aqueousdimethylformamide, or tetrahydrofuran at 40-100° C.

The compounds 1 where R is a polyfluoroalkyl group can be prepared from2-acetyl-3-hydroxythiophene-4-carboxylate following the cyclizationprocedure described by Riva et al., (Synthesis, 195-201, 1997) by directcyclization in the presence of anhydrous polyfluoroalkanoyl anhydridescatalysed by 1,8-diazabicycloundec-7-ene.

The compounds I where R₁ is a trifluoromethanesulphonyloxy group can besynthesized starting from compounds I where R₁ is a hydroxy group usingprocedures well known to those skilled in the art, by way of examplewithout limitation, using trifluoromethanesulphonic anhydride orN-phenyltrifluoromethanesulphonimide in aprotic solvents such as1,2-dichloroethane or other chlorinated solvents or toluene, at atemperature in the range between 20° C. and the temperature of reflux ofthe solvent (Hendickson et al., Tetrahedron Letters, 4607-4510, 1973).The N-oxides of the compounds I may be synthesized by simple oxidationprocedures known to those skilled in the art. The oxidation proceduredescribed in P. Brougham in Synthesis, 1015-1017 (1987) allowsdifferentiation of the two nitrogen atoms of the piperazine ring andboth the N-oxides and N,N′-dioxides to be obtained.

Preparation of the phenylpiperazines 8, which has not been described inthe literature, is well documented in the examples and uses syntheticprocedures well known to those skilled in the art, which comprise thesynthesis of the proper aniline through standard reactions and thesubsequent cyclization with bis-(2-chloroethyl)amine to afford thepiperazine following the method of Prelog (Collect. Czech.Chem.Comm.,5:497-502, 1933) or its variations (Elworthy, J. Med. Chem.,40:2674-2687, 1997).

DETAILED SYNTHESIS OF THE COMPOUNDS OF THE INVENTION

Below are some examples intended only to illustrate the invention so asdescribed in the test, with no intention to limit it.

EXAMPLE 1N-{3-[4-(5-Chloro-2-methoxyphenyl)1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]Pyran-3-carboxamide

a) 1-(5-Chloro-2-methoxyphenyl)-4-[3-(N-phthalimido)propyl]piperazine(Compound 1A)

A mixture of of 28.64 g of 1-(5-chloro-2-methoxyphenyl)piperazine, 44.6g of anhydrous potassium carbonate and 33.65 g ofN-(3-bromopropyl)phthalimide in 250 mL of acetonitrile was stirred atreflux for 8 hours. After cooling to 20-25° C., 800 mL of water wasadded under stirring and the resulting suspension was filtered bysuction yielding a yellowish solid, which was washed with 300 mL ofwater and crystallised from methanol affording 46.5 g of the titlecompound, melting at 131-133° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 7.78-7.82m 2H phthalimide H3, H6 7.64-7.78 m 2H phthalimide H4, H5 6.92 dd 1Hmethoxyphenyl H4 6.65-6.78 m 2H methoxyphenyl H3, H6 3.81 s 3H CH₃O3.71-3.89 m 2H CH₂N(CO)₂ 2.78-3.00 m 4H 3 and 5 piperazine CH₂s2.40-2.65 m 6H 2 and 6 piperazine CH₂s, CH₂CH₂CH₂N(CO)₂ 1.80-2.03 m 2HCH₂CH₂CH₂

b) 1-(3-Aminopropyl)-4-(5-chloro-2-methoxyphenyl)piperazineTrihydrochloride.2.15 H₂O (Compound 1B)

A solution of 20.7 g of Compound 1A and 8.6 mL of 85% hydrazine hydratein 300 mL of ethanol were stirred at reflux for 3.5 hours. Afterwards,the reaction mixture was cooled to 20-25° C., diluted with 400 mL ofwater, acidified with 37% hydrochloric acid (pH=1) and stirred for 0.5hour. The precipitated solid was collected by filtration and washed with1N hydrochloric acid followed by water. The filtrate was concentrated byevaporation in vacuo, filtered, made basic by addition of 35% sodiumhydroxide at 0-5° C. and extracted with diethyl ether. The organic layerwas washed with brine, dried on sodium sulphate and evaporated todryness in vacuo affording 13.6 g (96%) of the title compound as a base.Acidification of the solution of the base in chloroform with more thanthree equivalents of 3N ethanolic hydrogen chloride followed byevaporation to dryness in vacuo and crystallization of the residue fromethanol/diethyl-ether 10:3 yielded the title compound, melting at200-202° C.

¹H-NMR (200 MHz) spectrum  Solvent: DMSOd₆, Chemical shift (δ)11.20-11.50 br 1H NH⁻ 8.10-8.40 br 3H NH3⁺ 6.85-7.10 m 3H phenyl H3, H4,and H6 5.10 br 5.3H NH⁻, 2.15H₂O 3.79 s 3H CH₃O 3.35-3.65 m 4H 2piperazine CH2s 3.03-3.35 m 6H 2 piperazine CH2s, CH₂CH₂CH₂NH₃ ⁻2.80-3.03 m 2H CH₂CH₂CH₂NH₃ ⁻ 1.95-2.22 m 2H CH₂CH₂CH₂NH₃ ⁻

c) Methyl 2-acetyl-3-benzoyloxythiolphene-4-carboxylate (Compound 1C)

3.48 mL of benzoyl chloride was added dropwise to a solution of 5.0 g ofmethyl 2-acetyl-3-hydroxythiophene-4-carboxylate (prepared as describedin J. Chem. Soc. Perkin Trans I, 1986, 507) and 3.66 g of4-dimethylaminopyridine in 100 mL of dichloromethane at 20-25° C. andstirred for 2 hours. The mixture was washed with 0.5N hydrochloric acid,water (2×20 mL), 2.5% aqueous sodium bicarbonate (2×40 mL) and water(2×20 mL). The organic layer was dried with sodium sulphate, evaporatedto dryness in vacuo and purified by flash chromatography usingchloroform/ethyl-acetate (100:1). The yield of Compound 1C was 7.089, asa yellow deliquescent solid, which was used in the next step withoutfurther purification.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.36 s 1Hthiophene H5 8.20-8.42 m 2H phenyl H2, H6 7.52-7.78 m 3H phenyl H3, H4,H5 3.73 s 3H CH₃O 2.50 s 3H CH₃CO

d) Methyl 2-(2-bromoacetyl)-3-benzoyloxythiophene-4-carboxylate(Compound 1D)

A solution of 1.28 mL of bromine in 24 mL of tetrachloromethane wasadded dropwise to a solution of 7.23 g of Compound 1C in 72 mL oftetrachloromethane over a period of 10 minutes and stirred at reflux.After a further 5 minutes at reflux, the mixture was cooled to 20-25° C.The precipitated solid was collected by filtration and washed with coldtetrachloromethane to yield 7 g (77%) of Compound 1D, melting at115-118° C. The compound was contaminated with impurities 1B and methyl2-(2,2-dibromoacetyl)-3-benzoyloxythiophene-4-carboxylate (2% and 6%mol. respectively, determined by ¹H-NMR spectroscopy), but could be usedwithout further purification in the next reaction step.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.43 s 1Hthiophene H5 8.20-8.42 m 2H phenyl H2, H6 7.52-7.80 m 3H phenyl H3, H4,H5 6.70 s 0.06H CHBr₂ 4.30 s 1.84H CH₂Br 3.73 s 3H CH₃O 2.50 s 0.06HCH₃CO

e)2-[(3-Benzoyloxy-4-methoxycarbonyl)-2-thienyl]-2-oxoethyltriphenylphosphoniumBromide Hemihydrate (Compound 1E)

A solution of 6.9 g of compound 1D and 5.19 g of triphenylphosphine in45 mL of acetonitrile was stirred at reflux for 4 hours and then cooledto 20-25° C. The precipitate was collected by filtration to yield 10.27g (88%) of Compound 1E, melting at 150-152° C., which was pure enough tobe used in further reactions. 0.27 g of crude product was crystallizedfrom i-PrOH to yield 0.24 g of the analytical sample. M.p. (124)128-132°C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.38-8.50m 3H PhCO H2, H6 and thienyl H5 7.41-7.87 m 18h (C₆H₅)3P and PhCO H3,H4, H5 6.35 d 2H CH₂P 3.71 s 3H CH₃O

f) Methyl 7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxylate (Compound1F)

150 mL of 1M-aqueous sodium carbonate was added to a solution of 10.07 gof Compound 1E in 200 mL of 1,2-dichloroethane and the mixture wasstirred at 85° C. for 11 hours, then cooled. The organic layer wasseparated, washed with water to neutrality, dried over anhydrous sodiumsulphate and evaporated to dryness in vacuo to yield 8.67 g of a cruderesidue. The crude residue was purified by flash chromatography withpetroleum ether/ethyl acetate 6:4 to yield 4.1 g (92%) of Compound 1F,melting at 169-171° C. Compound 1F was crystallized from methanol togive the analytical sample. M.p. 169-171° C.

8.50 s 1H H2 7.95-8.05 m 2H phenyl H2, 6 7.50-7.60 m 3H phenyl H3, 4, 56.88 s 1H H6 4.00 s 3H CH₃O

g) 7-Oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxylic Acid (Compound 1G)

26 mL of 0.6N sodium hydroxide was added to a solution of 3.82 g ofCompound 1F in 174 mL of methanol and 87 mL of dioxane at 50° C. whilestirring. The mixture was stirred at 50° C. for an additional 20minutes, cooled to 20-25° C., then diluted with 280 mL of water,filtered and acidified with 1N hydrochloric acid to pH=1. The suspensionof that formed precipitate gel was stirred at 60° C. for 2 hours, untila heavier filtrable solid was obtained. This solid was filtered anddried to yield 3.4 g of the title compound, which was suitable for usein the next reaction step without further purification. It wascrystallized from ethanol to yield the analytical sample, melting at282-283° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 13.39 bs1H COOH 8.50 s 1H H2 8.00-8.05 m 2H phenyl H2, H6 7.52-7.60 m 3H phenylH3, H4, H5 7.13 s 1H H6

h)N-{3-[4-(5-Chloro-2-methoxyphenyl)-1-piperazinyl}-propyl]-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide

0.54 mL of 93% diethyl cyanophosphonate and 0.46 mL of triethylaminewere added to a solution of 0.82 g of Compound 1G and 0.94 g of Compound1B base in 15 mL of anhydrous N,N-dimethylformamide at 0° C. whilestirring. The mixture was stirred for 22 hours at 20-25° C., poured into150 mL of water. The solution was decanted and the pasty precipitatethat remained was dissolved in 60 mL of chloroform, washed with water,dried over sodium sulphate, and evaporated to dryness in vacuo.

The crude materials was purified by flash chromatography with ethylacetate/methanol (9:1) and evaporated to yield the pure title compound(1.2 g; 74%), which was crystallized from EtOAc. M.p. 165-166.5° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.45 s 1HH2 7.90-8.02 m 2H phenyl H2, H6 7.55-7.62 m 3H phenyl H3, H4, H5 7.45 t1H CONH 6.95 dd 1H chlorophenyl H4 6.83 s 1H H6 6.65-6.75 m 2Hchlorophenyl H3, H6 3.81 s 3H CH₃O 3.66 dt 2H CONHCH₂ 2.74-2.92 m 4H 2piperazine CH₂s 2.48-2.54 m 6H CH₂N and 2 piperazine CH₂s 1.80-2.00 m 2HCH₂CH₂CH₂

EXAMPLE 2N-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide

The title compound was prepared as described in Example 1 h, butsubstituting 1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine (preparedas described in patent GB 2,161,807) for Compound 1B. After pouring thereaction mixture into water and extracting with ethyl acetate, thecombined organic layers were washed with water (3×80 mL), dried oversodium sulphate and evaporated to dryness in vacuo. The crude productwas purified by flash chromatography with ethyl acetate/methanol(8.5:1.5) and evaporated to dryness. The residue yielded the pure titlecompound (1.4 g; 77%), which was crystallized from EtOAc to yield thetitle compound melting at 161-162° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.41 s 1HH2 7.90-8.02 m 2H phenyl H2, H6 7.50-7.65 m 4H NHCO and phenyl H3, H4,H5 6.80 s 1H H6 6.70-7.05 m 4H Chs of methoxyphenyl ring 3.83 s 3H CH₃O3.66 dt 2H CONHCH₂ 2.80-3.00 m 4H 2 piperazine CH₂s 2.48-2.62 m 6H CH₂Nand 2 piperazine CH₂s 1.80-2.00 m 2H CH2CH₂CH₂

EXAMPLE 35-Cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2-b]pyran-3-carboxamide

a) Methyl 2-acetyl-3-cyclohexanecarbonyloxythionhene-4-carboxylate(Compound 3A)

This compound was prepared as described for compound 1C of Example 1,but using cyclohexanecarbonyl chloride instead of benzoyl chloride. Thecrude product was purified by flash chromatography using a petroleumether/ethyl acetate gradient from 9:1 to 7:3 to afford Compound 3A(80%).

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.30 s 1Hthiophene H5 3.80 s 3H CH₃O 2.50 s 3H CH₃CO 1.00-3.00 m 11H cyclohexaneCHs

b) Methyl2-(2-Bromoacetyl)-3-cyclohexanecarbonyloxythiophene-4-carboxylate(Compound 3B)

A solution of 0.70 mL of bromine in 3.45 mL of acetic acid was addeddropwise over a period of 60 minutes to a solution of 3.56 g of Compound3A in 34.5 mL of acetic acid at 20-25° C. while stirring. After stirringfurther for 2.5 hours at 20-25° C., the mixture was poured into icewater and extracted with diethyl ether (2×80 mL). The combined organiclayers were washed with water (2×80 mL), 10% aqueous sodium carbonate(100 mL) and water (3×80 mL), dried over sodium sulphate and evaporatedto dryness in vacuo. The crude product was purified by flashchromatography in n-hexane/chloroform (6:4) to yield 1.31 g (29%) ofCompound 3B.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.36 s 1Hthiophene H5 4.29 s 2H CH₂Br 3.83 s 3H CH₃O 2.65-2.80 m 1H cyclohexaneCH 2.15-2.25 m 2H 2, 6 cyclohexane CHs (eq.) 1.85-1.95 m 2H 2, 6cyclohexane CHs (ax.) 1.25-1.80 m 6H 3, 4, 5 cyclohexane CH₂s

c)2-[(3-Cyclohexanecarbonyloxy-4-methoxycarbonyl)-2-thienyl]-2-oxoethyltriphenylphosphoniumBromide (Compound 3C)

A solution of 0.20 g of compound 3B and 0.13 g of triphenylphosphine in1.25 mL of acetonitrile was stirred at reflux for 2.5 hours and thencooled to 0-5° C. The precipitate was collected by filtration, thenwashed on the filter with a 2:1 mixture of ethylacetate/acetonitrile,followed by ethyl acetate, to yield 0.19 g (59%) of Compound 3C meltingat 165-167° C.

¹H-NMR (200 MNz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.31 s 1Hthiophene H5 7.55-8.00 m 15H (C₆H₅)₃P 6.35 d 2H CH₂P 3.79 s 3H CH₃O2.60-2.75 m 1H cyclohexane CH 1.95-2.05 m 2H 2, 6 cyclohexane CHs (eq.)1.10-1.70 m 8H other cyclohexane CHs

d) Methyl 5-Cyclohexyl-7-oxo-7H-thieno[3,2-b]pyran-3-carboxylate(Compound 3D)

A mixture of 0.16 g of Compound 3C, 2 mL of 1,2-dichloroethane and 2 mLof 1M aqueous sodium carbonate was heated at 45° C. for 36 hours. Aftercooling to 20-25° C., 5 mL of chloroform was added, the organic layerwas washed with water (2×10 ml,), dried on anhydrous sodium sulphate andevaporated to dryness in vacuo. The crude product was purified by flashchromatography (petroleum ether/ethyl acetate 1:1) yielding 0.05 g (68%)of Compound 3D as a white solid, melting at 114-119° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.43 s 1HH2 6.20 s 1H H6 3.94 s 3H COOCH₃ 2.55-2.70 m 1H cycloexane CH 1.15-2.15m 10H cycloexane CH₂s

e) 5-Cyclohexyl-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxylic Acid(Compound 3E)

0.3 mL of 1N sodium hydroxide and 1.0 mL of water were added to asolution of 0.040 g of Compound 3D in 1.8 mL of MeOH and 0.9 mL of1,4-dioxane at 20-25° C., while stirring. The mixture was heated at 50°C. for 3.5 hours. After cooling to 20-25° C., the mixture was dilutedwith water and acidified to pH 1 with 3N hydrochloric acid. Theprecipitated solid was collected by filtration and washed with water toafford 0.028 g (73.5%) of the title compound, melting at 269-275° C.

¹H-NMR (200 MHz) spectrum  Solvent: DMSO-d₆, Chemical shift (δ) 13.30 bs1H COOH 8.78 s 1H H2 6.23 s 1H H6 2.55-2.70 m 1H cycloexane CH 1.10-2.05m 10H cycloexane CH₂s

f)5-Cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2b]pyran-3-carboxamide

The title compound was prepared as described in Example 2, butsubstituting Compound 3E for Compound 1G. The crude product was purifiedby flash chromatography in ethyl acetate:2.7N methanolic ammonia (95:5).The residue, obtained after solvent evaporation from the collectedfractions containing the pure title compound (0.03 g; 73%) was dissolvedin 5 mL of MeOH and the opalescent solution was clarified with charcoal.Solvent evaporation yielded the pure title compound as a yellow pastysolid (67%).

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.41 s 1HH2 7.15 5 1H NH 6.85-7.10 m 4H methoxyphenyl Chs 6.21 s 1H H6 3.86 s 3HOCH₃ 3.60 q 2H NHCH₂ 3.00-3.15 m 4H 2 piperazine CH₂s 2.55-2.80 m 7H 2piperazine CH₂s, cyclohexane CH and CH₂CH₂CH₂ 2.05 dt 2H CH₂CH₂CH₂1.20-1.95 m 10H cyclohexane CH₂s

EXAMPLE 4N-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2b]pyran-3-carboxamide

a) Methyl 7-Oxo-5-trifluoromethyl-7H-thieno[3,2-]pyran-3-carboxylate(Compound 4A)

3.95 mL of trifluoroacetic anhydride and 9.2 mL of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added to a mixture of 4.10g of methyl 2-acetyl-3-hydroxythiophene-4-carboxylate and 14 mL ofpyridine at 0-5° C. The mixture was heated at 80° C. for 27 hours,during which time a total of 9.9 mL of trifluoroacetic anhydride and atotal of 9.2 ml and DBU were added in three additions. The mixture wascooled to 20-25° C., poured into a mixture of ice (250 g) and 37%hydrochloric acid (50 mL), and extracted with ethyl acetate (2×80 mL).The combined organic layers were washed with water, dried over sodiumsulphate and evaporated to dryness in vacuo. The residue was taken upwith petroleum-ether/ethyl-acetate (7:3) and filtered. The filtrate waspurified by flash chromatography using a petroleum ether/ethyl acetategradient (7:3 to 0:1). The residue was dissolved in diethyl ether,washed with 5% aqueous sodium carbonate and water, dried over sodiumsulphate and evaporated to dryness in vacuo to yield the title product(22%) melting at 148-158° C., which could be used in the next stepwithout further purification. The analytical sample was obtained bycrystallisation from ethanol. M.p. 163-164° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.58 s 1HH2 6.80 s 1H H6 3.96 s 3H COOCH₃

b) 7-Oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxylic Acid(Compound 4B)

A mixture of 0.70 g of Compound 4A, 5.6 mL of dioxane and 8.4 mL of 9Nhydrochloric acid was stirred at reflux for 75 minutes. After cooling to20-25° C., the precipated solid was filtered, washed with dioxane/water1:1.5 and water to afford 0.46 g of the title compound as a grey solidmelting at 249-251° C.

¹H-NMR (200 MHz) spectrum  Solvent: DMSO-d₆, Chemical shift (δ) 13.50 bs1H COOH 8.25 s 1H H2 7.19 s 1H H6

c)N-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxamide

The title compound was prepared as described in Example 2 substitutingCompound 4B for Compound 1 G. The crude product was purified by flashchromatography in ethyl acetate/2.7N ammonia in methanol (95:5)affording the title compound as a light-brown solid melting at 170-177°C. (33%).

¹H-NMR J(200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.55 s 1HH2 7.10 t 1H NH 6.85-7.10 m 4H methoxyphenyl Chs 6.80 s 1H H6 3.88 s 3HOCH₃ 3.60 l 2H NHCH₂ 2.90-3.15 m 4H 2 piperazine CH₂s 2.45-2.80 m 6H 2piperazine CH₂s, CH₂CH₂CH₂N 1.88 dt 2H CH₂CH₂CH₂

EXAMPLE 57-Oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7H-thieno[3,2-b]pyran-3-carboxamide

a) N-(3-Chloropropyl)-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide(Compound 5A)

This compound was prepared as described above, in Example 1, with thesubstitution of 3-chloropropylamine hydrochloride for Compound 1 B anddoubling the amount of triethylamine used. After dilution with water,the precipitated solid was filtered and, while still on the filter,washed with cold-water:dimethylformamide (2:1) and then with water. Thewashed solid was suspended in 10% aqueous sodium carbonate, stirred,filtered and washed with water to neutrality. Drying at 70° C. in vacuoyielded the title compound (95%).

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃ Chemical shift (δ) 8.52 s 1HH2 7.75-7.85 m 2H phenyl H2, H6 7.50-7.60 m 3H phenyl H3, H4, H5 7.00 s1H NH 6.80 s 1H H6 3.65-3.80 m 4H CH₂CH₂CH₂ 2.15 dt 2H CH₂CH₂CH₂

b)7-Oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7H-thieno[3,2-b]pyran-3-carboxamide

A mixture of 0.17 g of Compound 5A, 0.13 g of1-[2-(2,2,2-trifluoroethoxy)phenyl]-piperazine (prepared as described byEP 0748 800, G. Bantle et al.) and 0.07 g of potassium carbonate washeated at 200° C. for 20 minutes. After cooling to 20-25° C., the cruderesidue was purified by flash chromatography in ethyl acetate/methanolgradient (95:5 to 9:1) to yield 0.193 g (70%) of the title compound.M.p. 152-158° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.45 s 1HH2 7.80-7.95 m 2H phenyl H2, Hy 7.50-7.65 m 4H CONH, phenyl H3, H4, H56.80 s 1H H6 6.75-7.10 m 4H tribluoroethoxyphenyl CHs 4.44 q 2H CH₂O3.66 dt 2H CONHCH₂ 2.90-3.05 m 4H 2 piperazine CH₂s 2.50-2.70 m 6H CH₂Nand piperazine CH₂s 1.80-2.00 m 2H CH₂CH₂CH₂

EXAMPLE 6N-{3-[4-[2-Methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl7H-thieno[3,2-b]pyran-3-carboxamide

a) 1-t-Butoxycarbonyl-4-(5-hydroxy-2-methoxyphenyl)piperazine (Compound6A)

A solution of 8 g of 1-(5-hydroxy-2-methoxyphenyl)piperazinedihydrobromide and 3.17 g of anhydrous potassium carbonate in 30 mL ofwater was evaporated to dryness in vacuo. 100 mL of anhydroustetrahydrofuran and 5.18 g of 97% di-t-butyl dicarbonate (BOC₂O) wereadded to the residue and the mixture was stirred at 20-25° C. for 2hours, followed by addition of 100 mL of anhydrous tetrahydrofuran. Thesuspension was filtered and the filtrate evaporated to dryness in vacuo.The residue was dissolved in 200 mL of chloroform. The solution waswashed with 5% sodium bicarbonate (3×50 ml) and water (2×50 mL), anddried over sodium sulphate. The solvent was removed at reduced pressureand the residue was purified by flash chromatography in petroleumether/ethyl acetate (75:25) to yield 1.91 g (28.7%) of Compound 6A and1.58 g (35.7%) of1-t-butoxycarbonyl-4-(5-t-butoxycarbonyloxy-2-methoxyphenyl)piperazine.A solution of this by-product in 40 mL of methanol and 6 mL of 1N sodiumhydroxide was maintained overnight at 20-25° C. The mixture wasneutralized with acetic acid, solvent was removed at reduced pressureand the remaining residue was dissolved in 40 mL of chloroform. Afterwashing with water (3×10 mL) the organic layer was dried over sodiumsulphate and the solvent evaporated in vacuo to recover an additional1.15 g (17.2%) of Compound 6A as a thick oil (total yield 45.9%).

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 6.70 d 1HH3 of phenyl ring 6.45-6.53 m 2H H4 and H6 of phenyl ring 5.77 s 1H OH3.78 s 3H CH₃O 3.48-3.68 m 4H 2 piperazine CH₂s 2.82-3.05 m 4H 2piperazine CH₂s 1.48 2 9H (CH₃)₃C

b)1-t-Butoxycarbonyl-4-[2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl]piperazine(Compound 6B)

A mixture of 2.83 g of Compound 6A, 6.05 g of cesium carbonate and 2.95g of 2,2,2-trifluoroethyl p-toluenesulphonate in 60 mL of acetonitrilewas refluxed for 16 hours while stirring. The solvent was evaporated offat reduced pressure, 90 mL of brine was added to the residue, and themixture was extracted with ethyl acetate (3×40 mL). The organic layerwas washed with water (3×20 mL) and of brine (20 mL) and dried oversodium sulphate. The solvent was removed at reduced pressure and theresidue purified by flash chromatography in a petroleum ether/ethylacetate gradient (95:5 to 80:20). The solvents were removed in vacuo toyield 1.86 g (52%) of Compound 6B as a white solid. M.p. (98) 102-105°C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 6.77 d 1HH3 of phenyl ring 6.45-6.63 m 2H H4 and H6 of phenyl ring 4.28 q 2HCF₃CH₂O 3.84 s 3H CH₃O 3.53-3.68 m 4H 2 piperazine CH₂s 2.90-3.06 m 4H 2piperazine CH₂s 1.48 s 9H (CH₃)₃C

c) 1-[2-Methoxy-5-(2,2,2-trifluoroethoxy)phenyl]piperazine·1.9hydrochloride (Compound of 6C)

A solution of 2.42 mL of trifluoroacetic acid in 30 mL of anhydrousdichloromethane was added dropwise to a solution of 1.17 g of Compound6B in 40 mL of anhydrous dichloromethane at 3-5° C. while stirring. Themixture was maintained overnight at 20-25° C., washed with 2N sodiumhydroxide (2×30 mL) and extracted with 2N hydrochloric acid (3×15 mL).The aqueous acid layer was washed with diethyl ether (2×20 mL) broughtto an alkaline pH with 37% sodium hydroxide at 5-10° C., and extractedwith diethyl ether (3×30 mL). The organic layer was dried over sodiumsulphate and the solvent was removed in vacuo to yield 0.78 g (89%) ofcompound 6C base as a thick oil. A solution of the compound 6C base indiethyl ether was treated with coal, filtered and acidified by additionof 3.6N HCl in diethyl ether to yield the hydrochloride salt, which wasrecovered by filtration and crystallized from acetonitrile and ethanolto yield the analytical sample. M.p. (188) 202-208° C. (dec.)

1H-NMR (200 MHz) spectrum  Solvent: DMSO-d₆, Chemical shift (δ) 9.18 bs2.9H NH₂ ⁺ and NH⁺ 6.90 d 1H phenyl H3 6.67 dd 1H phenyl H4 6.59 d 1Hphenyl H6 4.66 q 2H CF₃CH₂O 3.74 s 3H CH₃O 3.18 bs 8H piperazine CH₂s

d)N-{3-[4-[2-Methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide

This compound was prepared as described above, in Example 5b, with theexception that Compound 6C was used in place of1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine. After cooling to 20-25°C., the crude residue was purified by flash chromatography in ethylacetate:2N ammonia in methanol (98:2) to yield the title compound (60%). M.p. 156-158° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.50 s 1HH2 7.80-7.95 m 2H phenyl H2, H6 7.40-7.80 m 4H CONH, phenyl H3, H4, H56.85 s 1H H6 6.75 d 1H trifluoroethoxyphenyl H3 6.40-6.55 m 2Htrifluoroethoxyphenyl H4, H6 4.30 q 2H CH₂O 3.80 s 3H CH₃O 3.65 dt 2HCONHCH₂ 2.50-3.10 m 10H piperazine CH₂s and CH₂N 1.85-2.10 m 2HCH₂CH₂CH₂

EXAMPLE 7N-{3-[4-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide

This compound was prepared as described in Example 5b, with theexception that 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine(prepared as described by G. Bantle et al. in EP 748 800, 1966) was usedin place of 1-[2-(2,2,2-trifluoroethoxy)-phenyl]piperazine. Aftercooling to 20-25° C., the crude residue was purified by flashchromatography in ethyl acetate/2N ammonia in methanol (95:5) to yieldthe title compound (74%). M.p. 189-191° C.

¹H-NMR (200 MHz) spectrum  Solvent: CDCl₃, Chemical shift (δ) 8.45 s 1HH2 7.80-7.95 m 2H Phenyl H2, H6 7.45-7.65 m 4H CONH, phenyl H3, H4, H56.80 s 1H H6 6.65-6.75 m 2H trifluoroethoxyphenyl CHs 6.60 dd 1Htrifluoroethoxyphenyl CH 4.35 q 2H CH₂O 3.65 dt 2H CONHCH₂ 2.80-3.00 m4H 2 piperazine CH₂s 2.50-2.70 m 6H CH₂N and 2 piperazine CH₂s 1.90-2.00m 2H CH₂CH₂CH₂

EXAMPLE 8 Determination of affinity for cloned α₁ adrenergic receptorsand 5-HT_(1A) serotoninergic receptors by radioligand binding assay

Determination of affinity for cloned subtypes of the α₁-adrenoceptor wasperformed in membranes from cells transfected by electroporation withDNA expressing the genes encoding each α₁-adrenoceptor subtype.

Cloning and stable expression of the α₁-adrenoceptor gene were performedas previously described (Testa et al., Pharmacol. Comm., 6:79-86, 1995and references). The cell membranes were incubated in 50 nM Tris, pH7.4, with 0.2 nM [³H]prazosin, in a final volume of 1.02 mL for 30minutes at 25° C., in the absence or presence of competing drugs (1pM-10 μM). Non-specific binding was determined in the presence of 10 μMphentolamine. Incubation was stopped by addition of ice-cold Tris bufferand rapid filtration through Schleicher & Schuell GF52 filters that hadbeen pretreated with 0.2%-polyethyleneimine.

Genomic clone G-21 coding for the human 5-HT_(1A)-serotoninergicreceptor was stably transfected in a human cell line (HeLa) (Fargin etal., J. Biol. Chem., 284:14848-14852, 1989). HeLa cells were grown asmonolayers in Dulbecco's modified Eagle's medium (DMEM), supplementedwith 10% fetal calf serum and gentamicin (100 μg/mL), at 37° C. in 5%CO₂. The cells were detached from the growth flask at 95% confluence bya cell scraper and were lysed in a buffer containing ice cold 5 mM Tris,5 mM EDTA (pH 7.4). The homogenates were centrifuged at 40,000×g for 20minutes and the membranes were resuspended in a small volume of ice-coldbuffer containing 5 mM Tris and 5 mM, EDTA (pH 7.4), and immediatelyfrozen and stored at −70° C. until use.

On the day of experiment, the cell membranes were resuspended in abuffer containing 50 mM Tris (pH 7.4), 2.5 mM MgCl₂, 10 μM pargyline(Fargin et al., Nature, 335:358-360, 1988). The membranes were incubatedin a final volume of 1 mL for 30 minutes at 30° C. with 1.2 nM[³H]8-OH-DPAT, in the absence or presence of test molecules.Non-specific binding was determined in the presence of 10 μM 5-HT.Incubation was stopped by addition of ice-cold Tris buffer and rapidfiltration through Schleicher & Schuell GF52 filters that had beenpretreated with 0.2%-polyethyleneimine.

Inhibition of specific binding of the radioligands by the test drugs wasanalyzed to estimate the IC₅₀ value by using the non-linearcurve-fitting program Allfit (De Lean et al., Am. J. Physiol.,235:E97-E102, 1978).

The IC₅₀ value was converted to an affinity constant (Ki) by theequation of Cheng et al., (Biochem. Pharmacol., 22:3099-3108, 1973).Data were expressed as mean of Ki.

RESULTS

The compounds of the invention exhibited the desired potency andselectivity at α₁ adrenoceptors, as shown in Table 1.

TABLE 1 Affinity (Ki, nM) of the different compounds tested forrecombinant α₁-adrenoceptor subtypes and 5-HT_(1A) receptor Human clonedreceptors Example α_(1a) α_(1b) α_(1d) 5-HT_(1A) 1 0.58 2.53 4.12 2 0.107.52 2.46 4.48 4 0.60 23.16 3.60 26.21 5 0.045 4.34 1.01 7.59 6 3.1939.31 48.17 1081.00 7 0.17 3.47 2.45 88.54 Compound A 0.60 3.29 2.844.53 Prazosin 0.61 0.42 0.23 >10000

EXAMPLE 9 In vitro evaluation of functional antagonism for α_(IL)adrenoceptors

The functional α₁-antagonistic activity of the test compounds againstnoradrenaline(NA)-induced contractions of rabbit aorta pretreated withchloroethylclonidine (α_(1L) receptor) was evaluated according to themethod of Testa et al., (J. Pharmacol. Exp. Ther., 281:1284-1293, 1997).Adult male New Zealand rabbits were sacrificed by cervical dislocation.The aorta was removed, placed in Krebs-Henseleit buffer and dissectedfree of adhering tissue. Rings were prepared from each artery (8 ringsper aorta, about 4-5 mm wide) and suspended in 20mL organ bathcontaining Krebs bicarbonate buffer of the following composition: 112 mMNaCl, 5.0 mM KC1, 2.5 mM CaCl₂, 1.0 mM KH₂PO₄, 1.2 mM MgSO₄, 12.0 mMNaHCO₃ and 11.1 mM glucose, equilibrated at 37° C. with 95% O₂: 5% CO₂.Desmethylimipramine (0.1 μM) and corticosterone (1 μM) to block neuronaland extraneuronal uptake of NA, (±)-propranol (1 μM) to block βadrenoceptors and yohimbine (0.1 μM) to block α₂ adrenoceptors wereadded to the buffer. The tissues were subjected to a passive load of 2 gand the tension developed was measured using isometric transducers(Basile 7003).

The preparations were equilibrated for 60 minutes and then primed every30 minutes with 10 μM NA for three times. The aortic rings were thenincubated with the alkylating agent chloroethylclonidine (50 μM) for 30minutes and then washed extensively three times, over a 30 min periodbefore constructing the NA-concentration/response curve. Followingwashing, tissue was re-equilibrated for 45 min. Test drug was added andafter 30 minutes, a second cumulative-NA-concentration/response curvewas constructed. Each antagonist concentration was tested using 2-3aortic rings from different rabbits.

Dose ratios (i.e., the ratio between the concentrations of noradrenalinerequired to produce half-maximal response in the presence and in theabsence of the test antagonist) were calculated at each concentration ofthe compounds. The logarithm of these dose ratio −1 was plotted againstthe logarithm of the compound concentrations (Schild plot) to evaluatethe affinity constant Kb.

When only one or two concentrations of the test compounds were utilised,the apparent Kb value was calculated using the formula: Kb=[B]/(DOSERATIO-1), where B is the antagonist concentration.

RESULTS

The compounds tested showed good affinity for the α_(1L) adrenoceptorsubtype. The data are expressed as pKb in Table 2.

TABLE 2 Functional affinity of the tested compounds for the α_(1L)adrenoceptor subtype Example pKb 1 8.17 2 8.85 4 7.92 5 9.12 7 8.66 CompA 8.64 Prazosin 8.11

EXAMPLE 10 Effects on urethral contractions induced by noradrenalineinjection and blood pressure in dogs after intravenous administration.

The experiments were performed according to the method of Imagawa et al.(J. Pharmacol. Methods, 22:103-111, 1989), with substantialmodifications, as follows: adult male beagle dogs, weighing 8-10 kg,were anaesthetized with pentobarbital sodium (30 mg/kg i.v. and 2mg/kg/h i.v.), intubated and spontaneously ventilated with room air. Inorder to monitor systemic blood pressure (BP), a polyethylene (PE)catheter was introduced into the aortic arch through the left femoralartery. A collateral of the left femoral vein was cannulated forinfusion of anaesthetic, and the right femoral vein was cannulated foradministration of compounds. For intraarterial (i.a.) injection ofnoradrenaline (NA), a PE catheter was introduced into the lower portionof the abdominal aorta via the right external iliac artery. Through suchprocedure, NA was selectively distributed to the lower urinary tract. Aparamedian vertical suprapubic incision extending from the base of thepelvis to the mid-abdominal region was made and the bladder and theprostate were exposed. The bladder was manually emptied with a syringe.Prostatic urethral pressure was monitored with a Mikro-tip catheter (5F)introduced into the bladder via the external urethral meatus, andwithdrawn until the pressure transducer was positioned in the prostaticregion of the urethra. A ligature was secured between the neck of thebladder and urethra to isolate the response of the latter and to avoidany interaction with the bladder. Another ligature was put around theMikro-tip catheter at the external meatus, to secure the catheteritself.

After a stabilizing period following the surgical procedure (30minutes), in which arterial and prostatic urethral pressures werecontinuously monitored as basal values, i.a. administration of NA wasmade at intervals of 20 minutes.

The NA doses were chosen to produce an increase of at least 100% inurethral pressure. The test compounds were administered intravenously ina cumulative manner with intervals of 15-20 minutes betweenadministrations. I.a. injections of NA were repeated 5 minutes afterevery dosing of test compound with intervals of about 10 minutes betweenstimulations. In order to compare the effects of the administeredcompound, dose/response curves (log dose transformation) wereconstructed by computing, at the peak effect, the percent decrease indiastolic blood pressure and percent inhibition of the increase inurethral pressure induced by NA. Linear regression equations were thenused in order to evaluate the theoretical effectiveness as ED₂₅ (theeffective dose inducing a 25% decrease in diastolic blood pressure) andID₅₀ (the dose inhibiting by 50% the increase in urethral pressure).

RESULTS

The effects obtained after intravenous administration of the compoundsof examples 1, 2 and 5 are shown in Table 3. Results obtained afterinjection of prazosin and Comp A are also shown in the table.

TABLE 3 Data represent the active doses (expressed in μg/kg) inhibitingby 50% the urethral contractions (UC) induced by noradrenaline (NA), theactive doses (expressed in μg/kg) in lowering diastolic blood pressure(DBP) and the ratio (DBP/US) between the active doses Compound UC ID₅₀NA DBP ED₂₅ Ratio 1 5.3 280 52.8 2 1.8 35.5 19.7 5 2.7 >1000 >370Prazosin* 3.6 6.6 1.83 Comp A* 2.4 243 101.2 *Data from Leonardi et al.,J. Pharmacol. Exp. Ther. 281:1272-1283, 1997.

The pharmacological results confirm that the compounds of the inventionare α₁₋adrenoceptor antagonists with good selectivity for the α₁adrenoceptor, compared to the 5-HT_(1A) receptor, and good affinity alsofor the α_(1L) subtype, as far as in vitro data are concerned.

The in vivo pharmacological results confirm the high uroselectivity ofthe compounds of the invention and justify their possible use in thetreatment of obstructive diseases of the lower urinary tract, includingBPH.

Effective Amounts

The following represent guidelines to effective oral, parenteral orintravenous dose ranges for human hosts, expressed in mg/kg of bodyweight per day, for use in obstructive disorders of the lower urinarytract:

General 0.001-20 Preferred 0.05-3 Most preferred 0.5-2

The most-preferred values refer to oral dosing. Intravenous dosagesshould be 10 to 100 fold lower. Selective-use dosages, i e., dosagesthat are active in the lower urinary tract without a substantial effecton blood pressure, depend on the particular compound employed.Generally, in the case of a compound selective in inhibiting urethralcontraction, up to four times the amount of the ED₅₀ used in inhibitingurethral contraction can be administered without substantial effect onblood pressure. Further refinements and optimization of dosages arepossible using simple routine experiments. The active compounds of theinvention may be orally administered, for example, with an inert diluentor with an edible carrier, or they may be enclosed in gelatine capsules,or they may be compressed into tablets. For the purpose of oraltherapeutic administration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompounds, but the amount of active ingredient may be varied dependingupon the particular form and may conveniently be between 5% and about70% of the weight of the unit. The amount of active compound in suchcompositions is such that a suitable dosage will be obtained althoughthe desired dosage can be obtained by administering a plurality ofdosage forms. The preferred compositions and preparations according tothe invention are prepared so that an oral dosage unit form containsbetween 1.0-300 milligrams of active compound. The tablets, pills,capsules, troches and the like may also contain, for example, thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatine; an excipient such as starch or lactose; adisintegrating agent such as alginic acid, sodium starch glycolate,cornstarch and the like; a lubricant such as magnesium stearate orhydrogenated castor oil, a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; and a flavoring agentsuch as peppermint, methyl salicylate, or orange flavoring. When thedosage unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier such as a fatty oil. Other dosageunit forms may contain other various materials which modify the physicalform of the dosage unit, for example as coatings. Thus, tablets or pillsmay be coated with sugar, shellac, or other enteric coating agents. Asyrup may contain, in addition to the active compounds, sucrose as asweetening agent and certain preservatives, dyes, coloring and flavors.The materials used in preparing these various compositions should bepharmaceutically pure and nontoxic in the amounts used. For the purposeof parenteral therapeutic administration, the active compounds of theinvention may be incorporated into a solution or suspension. Thesepreparations should contain at least 0.1% of active compound, but it maybe varied between 0.5 and about 30% of the weight thereof. The amount ofactive compound in such compositions is such that a suitable dosage willbe obtained. The preferred compositions and preparations according tothe present inventions are prepared so that a parenteral dosage unitcontains between 0.2 to 100 milligrams of active compound. The solutionsor suspensions may also include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates; citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteralmultiple-dose vials may be of glass or plastics material.

Additional compositions suitable for administration by various routesand containing compounds according to the present invention are alsowithin the scope of the invention.

Dosage forms, additional ingredients and routes of administrationcontemplated herein include those disclosed in the United States patentsU.S. Pat. No. 4,089,969 to Muchowsk et al. and U.S. Pat. No. 5,091,182to Ong et al., both incorporated by reference in their entirety.

What is claimed is:
 1. A method for the treatment of a patient sufferingfrom excessive intraocular pressure, the method comprising administeringan effective amount of a compound represented by the general formula I

wherein R is chosen from the group consisting of an aryl, cycloalkyl,and lower polyhaloalkyl group, R₁ is chosen from the group consisting oflower alkyl, lower alkoxy, lower polyfluoroalkoxy, hydroxy andtrifluoromethanesulfonyloxy group, each of R₂ and R₃ being independentlychosen from the group consisting of a hydrogen, halogen, lower alkoxy,and lower polyfluoroalkoxy group, and n is 0, 1 or 2, or apiperazine-N-oxide thereof or a pharmaceutically acceptable salt of anyof the foregoing to a patient in need of such treatment.
 2. The methodof claim 1 wherein the compound represented by the general formula I isadministered as a pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier.
 3. The method accordingto claim 1 or 2 wherein the compound represented by the general formulaI is selected from the group consisting ofN-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,5-cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxamide,7-oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-[2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-7H-thieno[3,2-b]pyran-3-carboxamide,andN-{3-[4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide.4. A method for the treatment of a patient suffering from cardiacarrhythmia, the method comprising administering an effective amount of acompound represented by the general formula I

wherein R is chosen from the group consisting of an aryl, cycloalkyl,and lower polyhaloalkyl group, R₁ is chosen from the group consisting oflower alkyl, lower alkoxy, lower polyfluoroalkoxy, hydroxy andtrifluoromethanesulfonyloxy group, each of R₂ and R₃ being independentlychosen from the group consisting of a hydrogen, halogen, lower alkoxy,and lower polyfluoroalkoxy group, and n is 0, 1 or 2, or apiperazine-N-oxide thereof or a pharmaceutically acceptable salt of anyof the foregoing to a patient in need of such treatment.
 5. The methodof claim 4 wherein the compound represented by the general formula I isadministered as a pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier.
 6. The method accordingto claim or/wherein the compound represented by the general formula I isselected from the group consisting ofN-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,5-cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxamide,7-oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-[2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,andN-{3-[4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide.7. A method for the treatment of a patient suffering from erectiledysfunction, the method comprising administering an effective amount ofa compound represented by the general formula I

wherein R is chosen from the group consisting of an aryl, cycloalkyl,and lower polyhaloalkyl group, R₁ is chosen from the group consisting oflower alkyl, lower alkoxy, lower polyfluoroalkoxy, hydroxy andtrifluoromethanesulfonyloxy group, each of R₂ and R₃ being independentlychosen from the group consisting of a hydrogen, halogen, lower alkoxy,and lower polyfluoroalkoxy group, and n is 0, 1 or 2, or apiperazine-N-oxide thereof or a pharmaceutically acceptable salt of anyof the foregoing to a patient in need of such treatment.
 8. The methodof claim 7 wherein the compound represented by the general formula I isadministered as a pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier.
 9. The method accordingto claim 7 or 8 wherein the compound represented by the general formulaI is selected from the group consisting ofN-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,5-cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxamide,7-oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-[2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,andN-{3-[4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide.10. A method for the treatment of a patient suffering from sexualdysfunction, the method comprising administering an effective amount ofa compound represented by the general formula I

wherein R is chosen from the group consisting of an aryl, cycloalkyl,and lower polyhaloalkyl group, R₁ is chosen from the group consisting oflower alkyl, lower alkoxy, lower polyfluoroalkoxy, hydroxy andtrifluoromethanesulfonyloxy group, each of R₂ and R₃ being independentlychosen from the group consisting of a hydrogen, halogen, lower alkoxy,and lower polyfluoroalkoxy group, and n is 0, 1 or 2, or apiperazine-N-oxide thereof or a pharmaceutically acceptable salt of anyof the foregoing to a patient in need of such treatment.
 11. The methodof claim 10 wherein the compound represented by the general formula I isadministered as a pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier.
 12. The method accordingto claim 10 or 11 wherein the compound represented by the generalformula I is selected from the group consisting ofN-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,5-cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxamide,7-oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-[2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,andN-{3-[4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide.13. A method for inhibiting cholesterol synthesis in a patient, themethod comprising administering an effective amount of a compoundrepresented by the general formula

wherein R is chosen from the group consisting of an aryl, cycloalkyl,and lower polyhaloalkyl group, R₁ is chosen from the group consisting oflower alkyl, lower alkoxy, lower polyfluoroalkoxy, hydroxy andtrifluoromethanesulfonyloxy group, each of R₂ and R₃ being independentlychosen from the group consisting of a hydrogen, halogen, lower alkoxy,and lower polyfluoroalkoxy group, and n is 0, 1 or 2, or apiperazine-N-oxide thereof or a pharmaceutically acceptable salt of anyof the foregoing to a patient in need of such treatment.
 14. The methodof claim 13 wherein the compound represented by the general formula I isadministered as a pharmaceutical composition comprising apharmaceutically:acceptable diluent or carrier.
 15. The method accordingto claim 13 or 14 wherein the compound represented by the generalformula I is selected from the group consisting ofN-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,5-cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxamide,7-oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-[2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,andN-{3-[4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide.16. A method for reducing sympathetically mediated pain in a patient,the method comprising administering an effective amount of a compoundrepresented by the general formula I

wherein R is chosen from the group consisting of an aryl, cycloalkyl,and lower polyhaloalkyl group, R₁ is chosen from the group consisting oflower alkyl, lower alkoxy, lower polyfluoroalkoxy, hydroxy andtrifluoromethanesulfonyloxy group, each of R₂ and R₃ being independentlychosen from the group consisting of a hydrogen, halogen, lower alkoxy,and lower polyfluoroalkoxy group, and n is 0, 1 or 2, or apiperazine-N-oxide thereof or a pharmaceutically acceptable salt of anyof the foregoing to a patient in need of such treatment.
 17. The methodof claim 16 wherein the compound represented by the general formula I isadministered as a pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier.
 18. The method accordingto claim 16 or 17 wherein the compound represented by the generalformula I is selected from the group consisting ofN-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,5-cyclohexyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-7-oxo-5-trifluoromethyl-7H-thieno[3,2-b]pyran-3-carboxamide,7-oxo-5-phenyl-N-{3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7H-thieno[3,2-b]pyran-3-carboxamide,N-{3-[4-[2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide,andN-{3-4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl}-7-oxo-5-phenyl-7H-thieno[3,2-b]pyran-3-carboxamide.